Abstract Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.
【저자키워드】 SARS-CoV-2, plasma, Immunity function, Longevity, 【초록키워드】 COVID-19, Inflammation, Mortality, aging, T cells, disease severity, variant, Comorbidities, polymorphism, Comorbidity, senescence, cytotoxicity, animal models, in vitro, Peripheral blood, Protein, T cell, immunomodulatory, therapeutic, Genotype, MCP-1, virus infection, early stage, single-nucleotide polymorphism, COVID-19 patients, Protective, Haplotype, Evidence, Inflammatory response, cell lines, CD69, Missense, COVID-19 patient, Recombinant protein, mononuclear cells, open, target cell, mononuclear cell, reduction, plasma concentration, Prognostic value, healthy control, infected cells, enrichment, individual, early stages, progression of disease, therapeutic use, contrary, rapid increase, SARS-CoV-2-infected cells, downregulation, circulating, IL-1B, lysates, homozygous, IL-18, lysate, BPIFB4, deleterious inflammation, inflammatory stimuli, minor alleles, TCD4, TCD8, susceptible, risk of COVID-19, event, selected, shown, develop, significantly, involved, healthy, characterized, less, demonstrated, correlated, significantly higher, homeostatic, minor allele, SARS-CoV-2-infected cell, single-nucleotide, 【제목키워드】 COVID-19, Level, Relevance,